Many clinical trials have suggested that fish intake or fish oil supplement can protect post-myocardial infarction patients against sudden cardiac death (anti-arrhythmic effects). However, there is also indication suggesting that fish oil may have pro-arrhythmic effects (increasing the recurrence of VT/VF in some patients with implantable cardioverter/defibrillator, and increasing the mortality in angina patients). The latter cases provide a strong warning sign: fish oil may not be suitable for certain patients. More mechanistic studies into the biological activity of fish oil supplement are needed. In particular, we need to know more about the effects of chronic treatment with long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs, active ingredients in fish oil) on cardiac electrical activity. This project is designed to study the mechanisms for the anti-arrhythmic and possible pro-arrhythmic effects of fish oil supplement. We believe relevant information can be obtained from a large animal (dog) model, focusing on diseased conditions that mimic the clinical situation in which fish oil supplement has been shown to provide an anti-arrhythmic efficacy. Furthermore, we believe such studies should include both acute application of n-3 PUFAs and chronic treatment, because both contribute to the clinical outcomes. We will test the following general hypothesis: chronic fish oil supplement produces anti- arrhythmic effects in infarcted hearts by modifying 'vulnerability factors' (vulnerability factors result from electrical and structural remodeling processes in infarcted hearts that promote arrhythmia), while acute effects of n-3 PUFAs can be pro-arrhythmic in diseased hearts when Na channel function and intercellular coupling are already compromised. Three Specific Aims are proposed to test the above hypothesis: Aims 1 & 2 will determine acute and chronic effects of fish oil supplement on the electrical and structural properties of normal dog hearts and dog hearts suffering from chronic ischemic cardiomyopathy (ICM), respectively. Aim 3 will determine the mechanism by which chronic fish oil supplement modifies 'vulnerability factors' in dog heart suffering from chronic ICM. The significance of this project derives from the new concepts and new approaches we take to address a seemingly 'old' question - why can fish oil supplement provide cardiac protection? Along the way, we will also address the new question: under what conditions can fish oil supplement lead to pro-arrhythmic effects? PROJECT NARRATIVE: This is a collaboration between basic scientists and cardiologists to address an 'old' question with new concepts and new approaches. Information from this project will help physicians make recommendation of fish oil supplement to coronary heart disease patients. [unreadable] [unreadable] [unreadable]